The cycle of cell growth, DMA synthesis, mitosis and cell division is the fundamental process by which cells (and all living organisms) grow, develop and reproduce. Hence, it is of crucial importance to science and human health to understand the molecular mechanisms that control these processes in eukaryotic cells. Molecular biologists have been extremely successful in identifying the major genes and proteins involved in this control system, especially in yeast cells where genetic tools are especially powerful. Indeed, the molecular details are so extensive and the regulatory network is so complicated that mathematical and computational methods are needed to reliably track the interactions of dozens of genes, mRNAs, proteins, and multi-protein complexes. Such a model of the cell cycle control system in budding yeast has proved to be both accurate and predictive. Nonetheless, as experimental characterization of cell-cycle control mechanisms continues to grow, the model must grow as well. In this proposal, a multi-disciplinary team of theoreticians and experimentalists from Virginia Tech, the Rockefeller University and the Institute for Molecular Oncology seeks a better understanding of the molecular controls over events at the end of the cell cycle, when replicated DMA molecules are partitioned to the two halves of a dividing cell so that each newly formed cell receives one and only one copy of each DNA molecule. If the dividing cell makes errors in this process, then newborn cells will inherit too many or too few DNA molecules, which is a root cause of some diseases-like cancer-and of some birth defects. The investigators will measure the molecular correlates of mitotic-exit events, and they will build detailed models of the signaling pathways that control these events (the mitotic-exit network, the 'FEAR1 pathway, the DNA-damage checkpoint, and the spindle assembly checkpoint). All models are built on a solid foundation of experimental observations, and they make clear and novel predictions about cell division under controlled conditions. Many of these predictions will be tested by the experimental collaborators. Because all eukaryotic cells seem to employ the same fundamental molecular machinery of cell cycle regulation, success in modeling mitotic exit in budding yeast will translate into better understanding of normal and aberrant cell division of relevance to human health: e.g., embryonic development, tissue regeneration, wound healing, and carcinogenesis. [unreadable] [unreadable] [unreadable]